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Biomedical subjects

D M Jackson

Publications and source records attributed to D M Jackson.

At least 19 recordsLinked to original sources
PubMed2000

GABA potentiation: a logical pharmacological approach for the treatment of acute ischaemic stroke.

It has been shown that enhancing the function of the major inhibitory neurotransmitter GABA decreases glutamatergic activity in the brain. Since increased glutamatergic activity is the major primary event that results in cell death following an acute hypoxic-ischaemic stroke, GABAmimetic drugs might therefore be expected to be neuroprotective. This review examines the evidence that GABAergic function is acutely depressed following an ischaemic insult, and also reviews the data that suggest that increasing cerebral GABA concentration has a neuroprotective effect, as does the administration of some (but not all) GABAmimetic agents. The GABA uptake inhibitor CI-966, the GABA(A) agonist muscimol and the GABA(A)mimetic clomethiazole have all been shown to be neuroprotective in animal models of stroke when given after the ischaemic insult. In contrast, benzodiazepines and particularly barbiturates, although potent GABA(A) potentiators, have shown little promise as neuroprotectants. The diversity of GABA(A) receptor subtypes and the in vivo efficacy of certain GABA(A) receptor ligands in animal models of stroke suggests that GABAmimetic drugs are an undervalued approach to stroke therapy.

Acute Disease↗
PubMed2000

Clomethiazole protects against hemineglect in a primate model of stroke.

Permanent occlusion of the M1 segment of the middle cerebral artery (pMCAO) in the marmoset, a New World species of monkey, produces unilateral functional deficits, including motor neglect with the contralesional arm and contralesional spatial hemineglect. In this study we examined whether clomethiazole, a drug which modulates the gamma-aminobutyric acid(A) receptor, reduced the severity of the hemineglect and other deficits in this primate model of stroke. Nine monkeys received pMCAO; 1 h later four of the nine were administered clomethiazole by intraperitoneal injection and subcutaneous implantation of osmotic mini-pumps, which released clomethiazole for 48 h. The monkeys had been trained and tested on a number of behavioral tasks prior to surgery and were re-tested 3 and 10 weeks later. Three weeks after pMCAO, monkeys treated with clomethiazole had a significantly reduced degree of spatial neglect compared to untreated controls. Clomethiazole was not effective against the severe contralesional motor impairment in the current study, although it ameliorated a somewhat less severe motor deficit in a previous study in which the more distal, M2 segment of the middle cerebral artery had been occluded. Postmortem analysis of the brains showed that clomethiazole treatment had significantly reduced the area of damage in part of the parietal cortex. These data suggest that clomethiazole may reduce the neglect that can be a debilitating consequence of right-sided stroke in man.

Animals↗
PubMed2000

The effect of dopamine on the rapidly adapting receptors in the dog lung.

The effect of an infusion of dopamine (50 microg/kg per min) on both resting and histamine-stimulated discharge of rapidly adapting receptors has been studied in the dog lung. In dogs pretreated with propranolol and phentolamine (1 mg/kg) dopamine inhibited the ability of histamine to stimulate the rapidly adapting receptors. This inhibition was attenuated by sulpiride, a selective D(2)antagonist, (0.5 mg/kg i.v.). Dopamine did not affect the increases in R(L)or the falls in C(dyn)produced by histamine. It is suggested that dopamine may play a role in the control of lung function by reducing the ability of sensory nerves to produce harmful reflex activity.

Adrenergic beta-Agonists↗
PubMed2000

Sublethal effects of resin glycosides from the periderm of sweetpotato storage roots on Plutella xylostella (Lepidoptera: Plutellidae).

Resin glycoside material extracted from the periderm tissue of storage roots from sweetpotato, Ipomoea batatas (L.) Lam., was bioassayed for effects on survival, development, and fecundity of the diamondback moth, Plutella xylostella (L.). The resin glycoside was incorporated into an artificial diet and fed to P. xylostella larvae. First instars were placed individually into snap-top centrifuge vials containing artificial diet with one of six concentrations of resin glycoside material (0.00, 0.25, 0.50, 1.00, 1.50, and 2.00 mg/ml). Each replication consisted of 10 individuals per concentration, and the experiment was repeated 13 times. Vials were incubated at 25 degrees C and a photoperiod of 14:10 (L:D) h in a growth chamber. After 6 d, surviving larvae were weighted and their sex determined, then returned to their vials. Later, surviving pupae were weighed and incubated at 25 degrees C until moths emerged. Females were fed, mated with males from the laboratory colony, and allowed to lay eggs on aluminum foil strips. Lifetime fecundity (eggs/female) was measured. There were highly significant negative correlations between resin glycoside levels and survival, and between glycoside levels and larval weight after 6 d of feeding. For larvae that lived at least 6 d, there was no additional mortality that could be attributed to the resin glycoside material. However, there was a significant positive correlation between glycoside dosages and developmental time of larvae (measured as days until pupation). Lifetime fecundity also was negatively affected at sublethal doses. Resin glycosides may contribute to the resistance in sweetpotato breeding lines to soil insect pests.

Animals↗
PubMed1999

An immunocytochemical approach to the study of beta-endorphin production in human keratinocytes using confocal microscopy.

Proopiomelanocortin (POMC) is a protein that is posttranslationally processed to yield POMC peptides. The main site of POMC expression is the anterior pituitary lobe but many other sources have been identified. There is evidence that the skin produces POMC peptides, although their roles have not yet been defined. In the skin, regulation of POMC gene expression is known to be hair-cycle dependent, and it is localized to the sebaceous gland. In particular, beta-endorphin, a POMC peptide, has been shown to be modulated by TPA, IL-1 alpha, and ultraviolet radiation in keratinocytes. These results were obtained by examination of POMC mRNA levels using the Northern blot method; beta-endorphin protein production by the Western blot method on cultured cells; and immunocytochemistry for tissue preparations. This report represents an approach to use immunocytochemistry to quantify beta-endorphin production in cultured human keratinocytes. Additionally, we examined whether exposure to 20 mJ ultraviolet B radiation (UVB) and/or UVA could influence beta-endorphin production in these cells. Keratinocytes were grown in monolayers, in serum-free medium, fixed, and incubated with antiserum to whole synthetic beta-endorphin. Fluorescence microscopy was performed with a confocal laser scanning microscope. The integrated level of fluorescence was evaluated in n = 18 +/- 8 individual cells, and this was assumed to be proportional to beta-endorphin content. High variability was observed in the fluorescence intensity among cells. No significant differences between control and UVB- or UVA + UVB-treated cells was found. Similar results were produced by using brefeldin A, a compound that disrupts the secretory pathway, eliminating the possibility that the absence of a difference between beta-endorphin content in the treated and control cells was due to secretion of the peptide into the medium. We conclude that: (1) beta-endorphin or beta-endorphin-like peptides are produced in human keratinocytes and are readily detected by immunocytochemistry; (2) under the conditions tested, UVA and/or UVB did not increase beta-endorphin-like immunoreactivity in these cells.

Cells, Cultured↗
PubMed1999

Molecular cloning, characterization, and promoter analysis of the human 25-hydroxyvitamin D3-1alpha-hydroxylase gene.

The human 25-hydroxyvitamin D3-1alpha-hydroxylase (1alpha-OHase) gene has been cloned. It contained nine exons and eight introns spanning approximately 6.5 kb and a 1.4-kb 5'-flanking region. The 5'-flanking region contains consensus or highly conserved sequences for TATA, Pu, and CCAAT boxes, four cAMP response elements, two activator protein-1 (AP-1) response elements, two AP-2 response elements, three specific protein-1 (Sp1) response elements, and four NF-kappaB binding sites, but no vitamin D response element. By using luciferase reporter gene constructs of truncated forms of the 1alpha-OHase promoter transfected into a modified pig kidney cell line, AOK-B50, we identified regulatory regions of the 1.4-kb 1alpha-OHase promoter for parathyroid hormone 1-34 [PTH(1-34)], forskolin, and 1,25-hydroxyvitamin D3 [1,25(OH)2D3]. The 1.4-kb 1alpha-OHase promoter (AN1) modestly (1.7-fold) induced luciferase activity, whereas 1,100- (AN2), 827- (AN3), 672- (AN4), 463-(AN5), and 363-bp (AN6)-truncated promoters greatly stimulated luciferase activity by 494-fold, 18.4-fold, 55.3-fold, 643-fold, and 56.4-fold, respectively. PTH(1-34) and forskolin stimulated the activity of all constructs to varying degrees with significantly greater responsiveness for both compounds on AN2 and AN5. 1,25(OH)2D3 suppressed PTH(1-34)-induced activity on AN2 and AN5 constructs by 58% and 52%, respectively, but had no effect on the other constructs. These studies characterize the regulatory regions of the human 1alpha-OHase gene and provide insight into the physiologic basis for regulation of the expression of this gene by PTH and 1,25(OH)2D3.

Base Sequence↗
PubMed1999

Clomethiazole (ZENDRA, CMZ) improves hind limb motor function and reduces neuronal damage after severe spinal cord injury in rat.

Clomethiazole (CMZ) has a neuroprotective effect in experimental focal and global forebrain ischemia. This neuroprotective effect may depend on its ability to enhance GABA receptor activity. We have studied the effect of pretreatment with CMZ on motor function recovery and nerve cell damage after spinal cord injury (SCI). Rats were randomized and 30 min before SCI they received a single intraperitoneal dose of CMZ (150 mg/kg) or saline. The spinal cord was injured with a 50 g (4.5 g/mm2) load, applied over the exposed dura, through a curved rectangular plate (2.2 x 5.0 mm) for 5 min at T8-9. The animals became paraplegic 1 day after injury. The rats were evaluated for recovery of hind limb motor function. All animals recovered to some extent over the observation period of 12 weeks. However, hind limb motor function was significantly better in the animals pretreated with CMZ. At 12 weeks the rats were killed and perfused/fixed for morphological investigations. Microtubule-associated protein 2 (MAP2) immunostaining was used to stain neurons and dendrites and Luxol-fast blue to stain myelinated tracts of the white matter. The injured segment of the spinal cord showed severe atrophy, distortion, cavitation and necrosis of grey and white matter. Compared to uninjured controls the transverse sectional area was reduced to 32.7 +/- 4% in untreated animals but only to 38.5% +/- 4.1 in CMZ-treated animals. MAP2 staining showed that, compared to uninjured controls, grey matter was reduced to 7.4 +/- 2.7% in saline-treated injured animals and to 22.7 +/- 5.4% in CMZ-treated rats. Our results thus show that in this model CMZ improves hind limb motor function and attenuates the morphological damage to the spinal cord.

Animals↗
PubMed1999

Synthesis and Pharmacology of the enantiomers of the potential atypical antipsychotic agents 5-OMe-BPAT and 5-OMe-(2,6-di-OMe)-BPAT.

The optically pure enantiomers of the potential atypical antipsychotic agents 5-methoxy-2-[N-(2-benzamidoethyl)-N-n-propylamino]tetralin (5-OMe-BPAT, 5) and 5-methoxy-2-{N-[2-(2,6-dimethoxy)benzamidoethyl]-N-n-propylamino}t etralin [5-OMe-(2,6-di-OMe)-BPAT, 6] were synthesized and evaluated for their in vitro binding affinities at alpha1-, alpha2-, and beta-adrenergic, muscarinic, dopamine D1, D2A, and D3, and serotonin 5-HT1A and 5-HT2 receptors. In addition, their intrinsic efficacies at serotonin 5-HT1A receptors were established in vitro. (S)- and (R)-5 had high affinities for dopamine D2A, D3, and serotonin 5-HT1A receptors, moderate affinities for alpha1-adrenergic and serotonin 5-HT2 receptors, and no affinity (Ki > 1000 nM) for the other receptor subtypes. (S)- and (R)-6 had lower affinities for the dopamine D2A and the serotonin 5-HT1A receptor, compared to (S)- and (R)-5, and hence showed some selectivity for the dopamine D3 receptor. The interactions with the receptors were stereospecific, since the serotonin 5-HT1A receptor preferred the (S)-enantiomers, while the dopamine D2A and D3 receptors preferred the (R)-enantiomers of 5 and 6. The intrinsic efficacies at the serotonin 5-HT1A receptor were established by measuring their ability to inhibit VIP-induced cAMP production in GH4ZD10 cells expressing serotonin 5-HT1A receptors. Both enantiomers of 5 behaved as full serotonin 5-HT1A receptor agonists in this assay, while both enantiomers of 6 behaved as weak partial agonists. The potential antipsychotic properties of (S)- and (R)-5 were evaluated by establishing their ability to inhibit d-amphetamine-induced locomotor activity in rats, while their propensity to induce extrapyramidal side-effects (EPS) in man was evaluated by determining their ability to induce catalepsy in rats. Whereas (R)-5 was capable of blocking d-amphetamine-induced locomotor activity, indicative of dopamine D2 receptor antagonism, (S)-5 even enhanced the effect of d-amphetamine, suggesting that this compound has dopamine D2 receptor-stimulating properties. Since both enantiomers also were devoid of cataleptogenic activity, they are interesting candidates for further exploring the dopamine D2/serotonin 5-HT1A hypothesis of atypical antipsychotic drug action.

Amphetamine↗
PubMed1999

The neuronal selective nitric oxide inhibitor AR-R 17477, blocks some effects of phencyclidine, while having no observable behavioural effects when given alone.

We have previously shown that the non-specific nitric oxide synthase inhibitor L-NAME blocks the behavioural effects of phencyclidine, but not d-amphetamine. To characterise the specificity of these effects, we used the specific neuronal nitric oxide synthase inhibitor AR-R 17477 in two rat models of psychosis: the prepulse inhibition of the acoustic startle response and locomotor activity. In biochemical assays, AR-R 17477 was shown to be selective for the neuronal nitric oxide synthase isoform. Test drugs were given subcutaneously. AR-R 17477 (0.5, 1 and 5 mg/kg) antagonised phencyclidine-induced hyperlocomotion, while higher doses (10 and 20 mg/kg) were less efficaceous. AR-R 17477 (1 mg/kg) antagonised phencyclidine-induced deficit in prepulse inhibition of the acoustic startle response, while a higher dose (15 mg/kg) was less active. AR-R 17477 did not affect startle amplitude or prepulse inhibition of the acoustic startle response, did not affect locomotion and did not induce any changes in gross behaviour (sniffing, rearing, etc.) as determined in a subjective observation study. AR-R 17477 (1 mg/kg) did not alter the effect of d-amphetamine in prepulse inhibition of the acoustic startle response. Using radiotelemetry in rats, L-NAME (10 mg/kg subcutaneously) increased blood pressure and decreased heart rate while AR-R 17477 (10 mg/kg) did not have any significant effect on these parameters. The results show that a neuronal nitric oxide synthase inhibitor antagonises the effects of phencyclidine on prepulse inhibition of the acoustic startle response and locomotor activity, without exhibiting significant behavioural effects of its own and suggest that our earlier results with L-NAME depended upon an inhibition of neuronal nitric oxide synthase and not on an inhibition of endothelial nitric oxide synthase or inducible nitric oxide synthase. The observed effects are unlikely to be related to an effect on cardiovascular function.

Amidines↗
PubMed1999

Electrophysiological comparison of 5-Hydroxytryptamine1A receptor antagonists on dorsal raphe cell firing.

Single-unit recording studies were undertaken in chloral hydrate-anesthetized rats to compare the effects on dorsal raphe cell firing of several putative 5-hydroxytryptamine (HT)1A receptor antagonists, including WAY 100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide), p-MPPI (4-(2-methoxyphenyl)1-[2'-[N-(2"-pyridinyl)-p-iodobenzamido]ethyl] pip erazine), and two newly described 5-HT1A receptor antagonists, NDL-249 [(R)-3-(N-propylamino)-8-fluoro-3, 4-dihydro-2H-1-benzopyran-5-carboxamide] and NAD-299 [(R)-3-N, N-dicyclobutylamino-8-fluoro-3, 4-dihydro-2H-1-benzopyran-5-carboxamide]. Consistent with a 5-HT1A receptor antagonist profile, pretreatment with an approximately equimolar (0.02-0.03 micromol/kg) i.v. dose of each compound caused a significant rightward shift in the dose-response curve for 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)tetralin]. Antagonist potency was clearly highest for NAD-299 and WAY 100635, which caused shifts roughly 3 times greater than those for either p-MPPI or NDL-249 (ED50 for 8-OH-DPAT, 1.3 +/- 0.3 microg/kg; after NAD-299, 18.2 +/- 1.0 microg/kg; after WAY 100635, 16.9 +/- 2.9 microg/kg; after NDL-249, 6.0 +/- 1.2 microg/kg; after p-MPPI, 4.7 +/- 1.1 microg/kg). In separate studies, each of the antagonists was administered alone in increasing cumulative doses to evaluate whether they possessed intrinsic agonist activity in this system. At doses below 0.01 micromol/kg, none of the drugs altered firing by more than +/-20% basal rates. At higher doses (>0.1 micromol/kg), WAY 100635, NDL-249, and NAD-299 caused a dose-dependent suppression of dorsal raphe cell firing (ED50 = 0.6 +/- 0.2, 0.7 +/- 0.3, and 0. 9 +/- 0.4 micromol/kg, respectively). However, the ED50 values for inhibition by these drugs were roughly 30 times higher than the doses that antagonized effects of 8-OH-DPAT. Moreover, the inhibition by all three antagonists (but not 8-OH-DPAT) was readily reversed by d-amphetamine (3.2 mg/kg i.v.), a releaser of norepinephrine, suggesting that these effects were likely due to alpha adrenergic receptor blockade rather than to 5-HT1A receptor agonism. Thus, it was concluded that WAY 100635, NAD-299, NDL-249, and p-MPPI all fulfill criteria as 5-HT1A receptor antagonists lacking intrinsic efficacy in the dorsal raphe system. The newly described compound NAD-299 exhibits antagonist potency comparable to that of WAY 100635 in this electrophysiological assay.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1998

Two selective 5-HT1A receptor antagonists, WAY-100 635 and NDL-249, stimulate locomotion in rats acclimatised to their environment and alter their behaviour: a behavioural analysis.

The aim was to study firstly, the motor effects of a new 5-HT1A antagonist, NDL-249 [(R)-3-(N-cyclopentyl-N-propylamino)-8-fluoro-3,4-dihydro-2H-1-benzopyra n-5-carboxamide hydrochloride] and of the reference 5-HT1A antagonist WAY-100 635 [N-(2-(1-(4-(2-methoxyphenyl)piperazinyl))ethyl)-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride], in comparison to the 5-HT1A agonist (+/-)-8-OH-DPAT [(8-hydroxy-2-(di-N-propylamino) tetralin, hereafter 8-OH-DPAT], in rats acclimatised to the automated activity cages; secondly, to study whether the behavioural effects of NDL-249 and 8-OH-DPAT are sensitive to the 5-HT depleting effects of p-chlorophenylalanine (PCPA); thirdly, to characterise the nature of the antagonist-induced activation seen in the automatic activity cages with the aid of a behavioural observation analysis; fourthly, to examine the interaction between the 5-HT1A receptors mediating the behavioural effects and dopamine (DA) receptors. NDL-249 was found to bind in vitro to rat hippocampal 5-HT1A receptors with high affinity and selectivity. In second messenger studies, it was devoid of agonist-like effects. In the locomotor activity studies, each antagonist significantly increased the incidence of horizontal activity, peripheral activity and rearing. 8-OH-DPAT, while significantly increasing peripheral and horizontal activities, decreased the incidence of rearing. PCPA blocked the motor effects of NDL-249 but did not affect those of 8-OH-DPAT. Observational analyses indicated that NDL-249 induced significant increases at one or more doses in sniffing, rearing and locomotion together with a significant reduction in stillness. WAY-100 635 significantly increased the incidence of rearing, intense grooming and vacuous chewing. The significant increases in sniffing, grooming and intense grooming and the significant decrease in stillness induced by the DA D1 agonist, SK&F 38393 [(+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride], were not altered by concomitant pre-treatment with NDL-249. Pre-treatment of rats with either the DA D1 antagonist SCH-23390 (2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol) or the DA D2 antagonist, raclopride, blocked the reduced stillness and increased sniffing and rearing induced by NDL-249. In conclusion, 5-HT1A antagonists including the new selective antagonist, NDL-249, induce mild behavioural activation in rats, which is mediated probably indirectly via DA systems.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1998

A pharmacological validation of radiotelemetry in conscious, freely moving rats.

Two reference substances were used in the present study. d-Amphetamine is a direct catecholamine-releasing agent which has a marked stimulant effect upon locomotor activity at low to moderate doses and induces stereotypy at higher doses. (+/-)8-Hydroxy-2-(di-n-propylamino)-tetraline [(+/-)8-OH-DPAT] is a selective 5-HT1A receptor agonist which produces a well-defined behavioral syndrome and a dose-dependent hypothermia. The first aim of this study was to validate that the d-amphetamine-induced activity monitored by telemetry correlated to that concomitantly measured in automated cages and complement these measures with an ethologically based direct observational technique. d-Amphetamine (2.5 and 5.0 micromol/kg s.c.) stimulated locomotion as assessed with radiotelemetry, in automatic cages and by observation. Accompanying these behavioral effects was a concurrent increase (assessed by radiotelemetry) in heart rate but not in blood pressure. The second part of this study examined the pharmacological effects of (+/-)8-OH-DPAT (0.09-6.1 micromol/kg s.c.) on behavior (observation and activity) and temperature and on the cardiovascular system. (+/-)8-OH-DPAT induced the classical serotonergic syndrome of lower lip retraction, forepaw treading, and flattened body posture (observation), and this was accompanied by a concomitant hypothermia (radiotelemetry). (+/-)8-OH-DPAT also induced a dose-dependent and significant decrease in heart rate for 50 min of the 1-h long observation period. This was not accompanied by an increase in blood pressure in spite of the increased activity as seen with all three methods. These results show that radiotelemetry can be used as a tool to measure activity, core temperature, and the cardiovascular parameters in animals that are less stressed than those that are restrained for similar more invasive measurements, and that this technique can be used in combination with others to produce a more complete ethogram of the animal's responses to pharmacological challenges.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1998

The discriminative stimulus effects of clomethiazole in the rat.

Rats were trained in a two-lever drug discrimination procedure using saline or clomethiazole (8 mg/kg, s.c. 15 min) as the training stimuli. A criterion of 9/10 days correct lever choice was adopted to select rats for substitution tests. The clomethiazole (CMZ) cue was not especially strong, and stable performance at this level was not achieved consistently. Nevertheless, in a series of substitution tests carried out in extinction, diazepam (3 mg/kg), chlordiazepoxide (10 mg/kg), phenobarbital (60 mg/kg), dizocilpine (0.1 mg/kg) and mianserin (3.0 mg/kg) were found to substitute for the training dose of CMZ. The first two of these produced a percentage choice of the drug lever equal to that produced by the training dose of CMZ (full generalization) whereas the latter three produced only partial generalization. Ethanol, muscimol, allopregnanolone, chlorpromazine and amitriptyline did not generalize to CMZ. CMZ is known to potentiate gamma-aminobutyric acid (GABAA) receptor function, a finding supported by the generalization to CMZ of the two benzodiazepines and phenobarbital. However, not all drugs acting at GABAA receptors generalized to CMZ. Although CMZ has no affinity for the N-methyl-D-aspartate (NMDA) receptor, it antagonizes a number of pharmacological responses mediated by NMDA receptors. The generalization in the drug discrimination procedure reported here support the suggestion that altering GABA activity can modulate NMDA-mediated responses. The lack of generalization after treatment with ethanol, chlorpromazine and amitriptyline suggests that the interoceptive cues are not mediated by a generalized sedation or drug-induced motor impairment.

Animals↗
PubMed1998

Rapid screening for penicillin susceptibility of systemic pneumococcal isolates by restriction enzyme profiling of the pbp2B gene.

Restriction digest profiling of pneumococcal pbp2b-specific amplicons was effective for screening penicillin resistance. The pbp2b amplicon of all pneumococcal isolates for which the MICs of penicillin were < or = 0.03 microgram/ml had one of two different susceptible restriction profiles, and all 33 isolates for which MICs were 0.5 microgram/ml or greater had one of seven distinct resistant profiles. Low-concentration penicillin resistance (MICs = 0.06 microgram/ml to 0.25 microgram/ml) was associated with sensitive HaeIII profiles in some isolates; however, RsaI profiling and pbp2b sequence analysis of such isolates revealed that some isolates contained low-level resistant pbp2b alleles, while others had susceptible pbp2b alleles. This data indicates that low-level penicillin resistance is sometimes conferred by determinants other than pbp2b.

Alleles↗
PubMed1997

Serotonergic modulation of 3,4-methylenedioxymethamphetamine (MDMA)-elicited reduction of response rate but not rewarding threshold in accumbal self-stimulation.

In a fixed interval 5-s rate-frequency function paradigm with rats, 3,4-methylenedioxymethamphetamine (MDMA; 0.5, 2 and 4 mg/kg) dose-dependently decreased response rate for nucleus accumbens self-stimulation while both D-amphetamine (0.3 and 1 mg/kg) and cocaine (5 and 15 mg /kg) increased response rates. The highest doses of MDMA caused a cessation of responding in many of the rats tested, but in those rats that continued to respond a significant reduction in frequency threshold for self-stimulation was seen. Cocaine and amphetamine dose-dependently reduced frequency threshold in all rats tested. The non-specific serotonin antagonist, methysergide (5 mg/kg), reversed the inhibitory effects of MDMA on response rates and caused all rats to respond following MDMA (4 mg/kg). Methysergide did not affect MDMA's threshold-lowering properties and when administered alone methysergide had not effect on self-stimulation. These results suggest serotonergic involvement in the performance but not reinforcement-modulating effect of MDMA in the self-stimulation paradigm.

Animals↗